The long-term goal of this project is to understand, at the molecular-level, the catalytic mechanism, stability and inhibition of ureases and through this understanding enhance our comprehension of enzyme catalysis, enzyme stability in extreme environments and the development of small-molecule therapeutics. The ureases are involved in a broad range of diseased states and a thorough understanding of the structure and function of this family of enzymes will impact our ability to modify the behavior of the ureases. The tools that will be used to reach our long-term goals are those of theoretical chemistry. The primary enzymes that will be studied are the ureases from K. aerogenes, B. pasteurii and H. pylori. The overarching biological questions we are addressing is how do ureases catalyze the conversion of urea to ammonia and carbamate at a rate that is 10/14> the uncatalyzed reaction as well as how does the urease from H. pylori give this bacterium the ability to survive the low-pH conditions of the gut. With the aid of theoretical tools the nature and energetics of urease-substrate interactions, urease-inhibitor interactions and reactions catalyzed by the ureases will be examined. Furthermore, we will examine the uncatalyzed decomposition and hydrolysis of urea in aqueous solution in order to understand where the ureases derive their catalytic power from. Moreover via MD simulations we will gain a better understanding of how enzymes (in particular the H. pylori urease can survive the low pH environment of the gut. The insights obtained into these processes will have a major impact on human health through the understanding of urease catalysis and inhibition.